Pregnant women with asthma should receive treatment with the same therapeutic effectiveness as that used outside of pregnancy to prevent exacerbations. Avoiding acute or chronic hypoxia is essential because maternal respiratory compromise can lead to fetal complications such as intrauterine growth restriction and preterm birth.

Guidance on the safety and management of asthma medications during pregnancy was reviewed by Delphine Beghin, PhD, PharmD, from the Centre de Référence sur les Agents Tératogènes (CRAT), Hôpital Armand Trousseau, Groupe Universitaire Est, Paris, France at the recent 30th edition of the French-Speaking Pneumology Congress, held at Lille Grand Palais in Lille, France.

The clinical course of asthma varies considerably throughout pregnancy. Approximately one third of patients experience improvement, one third remain stable, and one third worsen. Exacerbations are frequently associated with poor adherence when patients discontinue medications because of concerns regarding fetal safety.

Pregnancy and Pharmacokinetics of Medications 

Currently, the French National Agency for Medicines and Health Products Safety is reviewing the pregnancy pictograms on the packaging of teratogenic or fetotoxic medications. The review follows reports indicating that 70%-80% of medicines carry such warnings, but only 15%-30% are associated with a confirmed teratogenic risk.

Pregnancy-related physiologic changes do not warrant sudden halting of therapy. “The intention is good, the result calamitous,” noted CRAT in 2017.

Physiologic changes during pregnancy can influence drug pharmacokinetics. Slower gastric emptying, increased gastric pH, reduced intestinal motility, and nausea or vomiting may reduce the gastrointestinal absorption of oral drugs.

The increase in circulating blood volume of 40%-50%, which peaks at 30-34 weeks of gestation, expands the volume of distribution and may dilute circulating drug concentrations. A reduction in maternal serum albumin levels can increase the free fraction of drugs bound to plasma proteins. Changes in hepatic enzyme activity, including cytochrome P450 enzymes and uridine diphosphate glucuronosyltransferases, may alter drug metabolism depending on the specific molecule. Increased renal blood flow and glomerular filtration rates can enhance renal elimination.

“Regarding asthma treatments,” noted Beghin, “these physiologic changes do not justify systematic dose adjustment during pregnancy. The exceptions are theophylline and aminophylline, which are now less commonly used drugs. Reduced protein binding may increase maternal concentration, and close monitoring is required because of the narrow therapeutic range. For other treatments, including biologic therapies, no dose adjustments have been reported.”

Risk Periods 

Two key periods of risk have been identified during pregnancy. The embryonic phase, covering the first 10 weeks of amenorrhea, is the period of maximum sensitivity to the teratogenic effects of drugs, when drug exposure may interfere with organogenesis and lead to congenital malformations.

The second phase is the fetal phase, from 10 weeks of gestation to term,. This phase is associated with impaired organ maturation and growth, with potential functional consequences. Drug exposure during this period may also lead to neonatal effects related to the pharmacologic action of treatment, similar to adverse effects observed in adults.

Steroid Use 

Corticosteroids can be used throughout pregnancy, regardless of the route or dosage. Data on early pregnancy exposure do not show an increased risk for congenital malformations. Previous reports suggesting an association with facial clefts have not been confirmed. Therefore, corticosteroids can be prescribed, either inhaled or orally, in the first trimester.

No specific fetal or neonatal monitoring is recommended for the use of inhaled corticosteroids. Inhaled therapy is not associated with fetal or neonatal complications in the second and third trimesters because systemic absorption is low. Intrauterine growth restriction with prolonged systemic use has been reported, although the contribution of underlying maternal disease cannot be excluded.

A rare risk for acute neonatal adrenal insufficiency has been described, mainly in the context of corticosteroids used for fetal lung maturation rather than asthma treatment.

In practice, “for the inhaled route, no specific fetal or neonatal monitoring is recommended. For systemic administration, when treatment is administered at the end of pregnancy, neonatal monitoring may be considered, including weight, duration of clinical adaptation, and blood glucose levels, during the first few days of life. Prednisone, prednisolone, and methylprednisolone are preferred because of the larger volume of data in the literature,” Beghin summarized.

Beta Agonists 

Among short-acting beta-2 agonists, the most robust data are available for salbutamol and terbutaline, with fenoterol as a second-line option. Clinical and preclinical data have shown no risk for malformations. After inhalation, systemic absorption remains low at approximately 10%. However, systemic administration at the end of pregnancy may cause transient fetal or neonatal effects, such as tachycardia and blood glucose disorders.

“The therapeutic approach should prioritize the maintenance of respiratory stability. First-line treatment favors molecules with the longest safety history and a pharmacokinetic profile that promotes minimal systemic impact,” Beghin said.

Among long-acting beta-2 agonists, salmeterol and formoterol are the first-line options, either alone or in combination with inhaled corticosteroids, such as fluticasone or budesonide. These agents show no risk and result in minimal systemic exposure. Second-line agents, including indacaterol, vilanterol, and fenoterol, have fewer clinical data but no concerning findings.

Anticholinergics and Montelukast 

Clinical data on the use of inhaled anticholinergic agents during pregnancy are limited. Animal studies have not identified teratogenic effects, and substantial clinical experience exists for ipratropium, which has been in use for more than 20 years. The available evidence does not indicate major concerns regarding fetal or neonatal effects. Systemic absorption after inhalation remains low at approximately 10%, supporting its use when needed, with ipratropium being the preferred choice.

Montelukast is supported by extensive data, including more than 1000 prospectively exposed individuals in epidemiologic studies with control groups, confirming an acceptable safety profile during pregnancy.

Biologic Therapy 

Five biologic therapies have been approved in France for asthma or chronic obstructive pulmonary disease: omalizumab, mepolizumab, dupilumab, benralizumab, and tezepelumab. The long half-lives of these agents require careful consideration because discontinuation does not immediately stop fetal exposure.

“Their prolonged plasma half-life requires particular attention,” noted Beghin. “Discontinuing treatment does not immediately stop embryonic, fetal, or neonatal exposure. The child will therefore remain exposed via maternal circulation and will need to eliminate the drug over an extended period after birth, which should be considered during pediatrics monitoring.”

The placental transfer of monoclonal antibodies (mAbs) is facilitated by the neonatal Fc receptor (FcRn). FcRn is expressed on syncytiotrophoblast cells from approximately 14 weeks of gestation, and transport increases through the third trimester. FcRn binds to the Fc region of immunoglobulin (Ig)G1, IgG2, and IgG4, allowing IgG1 to cross most efficiently. 

“Fetal transfer therefore begins around 14 weeks of amenorrhea, after the end of organogenesis, which is the period of greatest sensitivity to teratogenic effects. Placental transfer is minimal in the first trimester,” Beghin said, “which reduces the risk of malformations, despite limited clinical data for some molecules. The volume of available data varies according to gestational age at exposure and cohort size; however, the known transfer mechanisms provide a reassuring basis for assessing the teratogenic risk. The elimination half-life of these mAbs is approximately 20 days. Achieving 97% elimination requires five half-lives or approximately 2-3 months. Preclinical studies in monkeys have not shown teratogenic effects.”

In animal models, in utero exposure to some antibodies, including benralizumab, is associated with transient depletion of polymorphonuclear leukocytes and eosinophils, which may persist for up to 6 months. In humans, neonatal plasma concentrations have only been reported for omalizumab, although transplacental transfer is expected for all agents and neonatal levels sometimes exceed maternal concentrations.

Prospective clinical data are the most robust for omalizumab, with approximately 300 individuals exposed to severe asthma during the first and later trimesters of pregnancy.

However, clinical data for other agents are limited. Some manufacturers maintain registries that have not yet been published. At CRAT, data are collected from individuals identified during clinical consultations, with follow-up of pregnancy outcomes.

“The numbers for benralizumab are comparable to those reported in the literature. Two malformations were observed in our study with dupilumab. The first case, tetralogy of Fallot, occurred in a patient who started treatment at 9 weeks of gestation after cardiac organogenesis, which excludes a causal role for the drug. The baseline risk of major congenital malformations is 2%-3% in the general population, and no treatment carries a risk of 0% or 100% (25% for isotretinoin, for example). This patient also had diabetes, a known risk factor for cardiac malformations. The second case involved concomitant treatment with upadacitinib, for which data during pregnancy are limited. No direct link with dupilumab can be established,” Beghin said.

“Given the absence of placental transfer before the end of organogenesis, no specific risk for malformations is expected for these molecules when administered after this period”, she added.

“If biologic therapy needs to be initiated during pregnancy, omalizumab should be the preferred choice because of its more extensive clinical experience,” Beghin emphasized.

Clinical Management 

If pregnancy is planned, preconception counseling is essential for biologic therapies, including a discussion of therapeutic alternatives and the balance between disease control and potential fetal risk. Treatment may be continued until early pregnancy is confirmed without concern for malformations, given the absence of placental transfer before 14 weeks’ gestation.

If pregnancy is identified during treatment and no suitable alternative exists, continuation should be considered when disease control is essential.

From the second trimester onward, placental transfer increases with gestational age. The care team should be informed about the ongoing treatment and its potential effects. For some agents, including benralizumab, transient reductions in neutrophils and eosinophils have been reported in newborns without clinical consequences, and a complete blood cell count should be considered.

Because of its prolonged half-life, early discontinuation in the third trimester may reduce neonatal exposure. However, if disease stability does not allow for discontinuation, treatment may be continued until delivery with appropriate neonatal monitoring, particularly if unexplained clinical signs occur.

“If biologic therapy needs to be initiated during pregnancy, omalizumab should be the preferred choice because of its extensive clinical experience”, Beghin said. Its safety is well documented, and its efficacy is comparable to that of other mAbs. For individuals who do not respond to omalizumab, other biological therapies may be considered, although clinical data on their use during pregnancy remain limited.

Beghin reported having no relevant conflicts of interest.

This story was translated from Medscape’s French edition.